Birt HoggDube Syndrome

Synonyms:

None

Etiology:

Mutation in the folliculin gene, chromosome 17p11.2

Associations:

Fibrofolliculomas, trichodiscomas, acrochordons, pulmonary cysts with spontaneous pneumothorax, renal carcinoma, and colorectal carcinoma in some kindreds

Clinical:

Skin-colored papules of face, neck, ears, and upper trunk, with intertriginous soft papules

Histology:

Trichodiscoma—interfollicular ovoid nodule with spindled cells in loose fibrillary stroma

Fibrofolliculoma—central follicle with extension of irregular epithelial strands into surrounding well-defined cellular fibrous stroma

IHC:

CD34+, S100-

Evaluation:

Abdominal and chest CT

Treatment:

Early tumor excision, laser resurfacing of facial lesions for cosmetic improvement

Prognosis:

Excellent with early diagnosis and vigilant monitoring

In 1977, Birt, Hogg, and Dube described a kindred of 70 individuals, some of whom presented with small skin-colored papules, predominantly of the face. These developed in early adulthood, and were noted to be inherited in a dominant pattern (1). The histomorphology of the papules was described as "abnormal hair follicles with epithelial strands extending out from the infundibulum of the hair follicle into a hyperplastic mantle of specialized fibrous tissue." The authors applied the term fibrofollicu-loma to these lesions. Also described in these patients were trichodiscomas and acrochordons. Trichodiscoma is a benign tumor of perifollicular mesenchyme. It is thought to represent a proliferation of the haarscheibe (hair disk), a perifollicular "richly vascularized dermal pad covered with thick epidermis containing Merkel cells and supplied by a thick myelinated nerve the branches of which end at the lower epidermal surface and on the blood vessels of the dermal pad" (2). It is composed of a dermal interfol-licular proliferation of spindle cells in a loose connective tissue matrix with varying amounts of mucin. It may have an orientation parallel to the skin surface. The haarscheibe is thought to represent a mechanoreceptor in animal skin. Its significance in humans is uncertain. The acrochordons reported in the original description of the syndrome were reported to have histologic findings typical of acrochor-dons (1). However, a subsequent study suggests that they have pathologic features of fibrofolliculoma and trichodiscoma (3).

The original kindred described by Birt, Hogg, and Dube had several individuals who developed hereditary medullary carcinoma of the thyroid. This tumor susceptibility was apparently inherited from an individual without the syndrome. Subsequent series have confirmed that thyroid carcinoma is not a part of the syndrome. While there were no internal manifestations of the syndrome in the original report, there have been subsequent descriptions of renal tumors. These include chromophobe renal cell carcinomas, hybrid tumors with features of chromophobe carcinoma and oncocytoma, oncocytoma, clear cell renal cell carcinoma, and rarely, papillary carcinoma (4). Additional associations include pulmonary cysts with spontaneous pneumothorax (5), collagenomas (6), lipomas (7), angiolipomas (7), oral fibromas (8), parathyroid adenomas (7) including oncocytoma (9), and flecked chorioretinopathy (10). Colonic polyps and adenocarcinoma have been reported, but appear to occur in only some affected families (11,12). In the largest series of BHD kindreds, with 152 patients, no such cases were reported (5).

The Birt-Hogg-Dube (BHD) gene has been mapped to chromosome 17p11.2 (13,14). It encodes a novel protein, folliculin, which is highly conserved across species (15). Mutations in the BHD gene result in formation of a truncated protein. Expression of BHD gene mRNA occurs in a wide variety of normal and neoplastic human tissue, but is markedly reduced in BHD renal tumors, suggesting that the BHD gene product may serve as a tumor suppressor gene (16). Based on studies in a rat model of inherited renal carcinoma, a germ line mutation is likely transmitted as a heterozygote, with the homozygous form being lethal in fetal life. A "second hit" in the normal gene copy is required for tumorigenesis. This second hit causes loss of heterozygosity. In this scenario, only the abnormal gene product is expressed, and there is a loss of expression of the normal gene copy. This causes a lack of production of a functional protein product that would aid in tumor sup pression. The second hit can be caused by a somatic mutation in the normal gene copy, which would result in loss of the normal gene product (17). Alternatively, expression of the normal gene copy may be suppressed by methyla-tion of the gene promoter region. Somatic inactivation of the BHD gene in sporadic renal cell carcinoma and colorectal carcinoma has been reported, implicating its role in the development of a subset of these tumors (18). A deletion in exon 4 of the BHD gene causes primary spontaneous pneumothorax without other features of BHD syndrome (19).

The fibrofolliculomas (FF) and trichodiscomas (TD) of Birt-Hogg-Dube syndrome usually develop in early adulthood. These patients present with small skin-colored or white papules that have a predilection for the face, neck, ears, and upper trunk (Figure 14.1A and 14.1B). Acrochor-dons typically develop in intertriginous areas. The clinical

Trichodiscoma
Figure 14.1. (A and B) Trichodiscomas and fibrofolliculomas: dome-shaped skin-colored papules.

Table 14.1. Clinical Differential Diagnosis of Facial Papules

Distribution

Onset

Associated Features/Syndrome

Trichodiscoma fibrofolliculoma

Syringoma

Basaloid follicular hamartoma

Angiofibroma

Trichoepithelioma Tricholemmoma

Diffuse involvement of face, extrafacial involvement Periocular prominence Diffuse involvement of face, may have extrafacial involvement Central face

Central face Nose, cheeks

Adulthood Birt-Hogg-Dubé syndrome

Adulthood Yellow hue

Variable +/- Pigment, comedos,

+/-alopecia

Childhood Tuberous sclerosis

Red hue, periungual fibromas, Shagreen patch Adolescence Skin-colored, varied lesion size Adulthood Cowden's syndrome

Tendency for epidermal change, cobblestone mucosa, acral keratoses differential diagnosis of the facial papules includes trichoepithelioma, angiofibroma, tricholemmoma, basaloid follicular hamartoma, and syringoma. There are several clinical features that may help distinguish these entities (Table 14.1), but histopathologic evaluation is required for definitive diagnosis.

Trichodiscoma is an ovoid superficial dermal nodule filling an interfollicular space (Figure 14.2). There is generally epidermal flattening, with interwoven fascicles of fibrillar collagen with spindled cells in a loose stroma that contains varying amounts of mucin and vascularity. Fibrofolliculoma may contain a similar mesenchymal component, but has a central distorted follicle from which thin epithelial strands extend in a sometimes retiform configuration, invested within a well-defined cellular fibrous stroma with spindled cells (Figure 14.3). Much of the spindle cell component of both lesions is highlighted by antibodies to CD34, supporting perifollicular mesenchyme as the histogenic origin of both lesions (20). The histomorphology of fibrofolliculoma is specific, but that of trichodiscoma is not. The differential diagnosis includes neurofibroma, to which it may show considerable similarity. Neuro-fibroma and trichodiscoma both display immuno-reactivity with antibodies to CD34, but elements of neurofibroma will also label with antibodies to S100 protein. Clinical presentation also helps distinguish these two entities.

Figure 14.2. Trichodiscoma: periadnexal collagen is arranged in lamellae, with spindle cells and increased mucin.

Figure 14.2. Trichodiscoma: periadnexal collagen is arranged in lamellae, with spindle cells and increased mucin.

Trichodiscomas
Figure 14.3. Fibrofolliculoma, perifollicular dense collagen within which are embedded thin follicular epithelial strands.

Once the diagnosis of multiple fibrofolliculomas and trichodiscomas has been made, a workup for underlying disease is mandatory, particularly because of the association of the syndrome with renal carcinoma. A suggested evaluation is given in Table 14.2.

Management of the Birt-Hogg-Dubé syndrome is aimed at early detection and treatment of tumors and pneumothorax. Treatment of cutaneous lesions is principally of cosmetic importance. Laser skin resurfacing of the face may result in significant improvement in appearance (21).

Birt-Hogg-Dubé syndrome is a more recently recognized cancer-susceptibility syndrome that is of particular importance because of the potential for early recognition based on typical cutaneous findings. The benefits of diagnosis may be life-saving not only for the index patient, but also for entire kindreds.

Table 14.2. Evaluation/management of the patient with Birt-Hogg-Dubé syndrome

1. Abdominal CT with contrast with attention to kidneys

2. Chest CT to evaluate for pulmonary cysts

3. Lower gastrointestinal tract evaluation for polyps/carcinoma age appropriate or as otherwise warranted based on family history

4. Patient education regarding informing relatives of disease with attendant risks

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Responses

  • Kevin
    What is periungual fibromas?
    7 years ago

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